JP2013523660A - Transdermal delivery patch - Google Patents

Abstract

A composition suitable for use in the production of a transdermal delivery patch for administration of a bioactive compound, the composition comprising a tocopherol phosphate compound and a polymeric carrier.
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Description

  The present invention relates to compositions suitable for use in the production of transdermal delivery patches for administration of bioactive compounds, and transdermal delivery patches comprising such compositions or matrix layers.

  Where the document, law or knowledge item is referenced or discussed herein, this reference or discussion is made available to the public on the priority date, where the document, law or knowledge item, or any combination thereof, It is not an admission that it has been known to the public and is known to be part of common general knowledge or related to attempts to solve any problem to which this specification pertains.

  Drug delivery is a method or process for administering pharmaceutical compounds to achieve therapeutic effects in humans and animals. Drug delivery technologies have been developed to improve the bioavailability, safety, duration, onset or release of pharmaceutical compounds. When developing drug delivery technologies, the problems you might encounter are compatibility of drug delivery systems and pharmaceutical compounds, maintaining appropriate and effective duration, potential side effects, patient convenience and compliance including. As a result, many drug delivery techniques do not reach the desired improvements or requirements. Thus, there remains a need for alternative drug delivery systems that effectively deliver drugs and other bioactive compounds.

  The present invention relates to compositions suitable for use in the production of transdermal delivery patches for administration of bioactive compounds, and transdermal delivery patches comprising such compositions or matrix layers.

  Accordingly, a first aspect of the present invention provides a composition suitable for use in the production of a transdermal delivery patch for administration of a bioactive compound, the composition comprising a tocopherol phosphate compound and a polymeric carrier. To do.

  The composition may be a matrix layer in a transdermal delivery patch.

  The present invention also provides the use of the composition or matrix layer in a transdermal delivery patch for administration of a bioactive compound.

  It was a surprising discovery that bioactive compounds can be efficiently administered using transdermal delivery patches.

  A second aspect of the present invention provides a transdermal delivery patch for administration of a bioactive compound containing the composition or matrix layer. The composition or matrix layer may be a solid or semi-solid layer. The transdermal delivery patch may have an additional layer.

A third aspect of the present invention is a method of preparing a transdermal delivery patch for administration of a bioactive agent, comprising:
(i) combining the polymer carrier and any inert single component with a suitable solvent;
(ii) combining a dispersion containing a physiologically active compound and a phosphate compound of tocopherol with the product of (i);
(iii) stirring the product of (ii) until completely uniform;
(iv) placing the composition of (iii) on the surface of a suitable mold or casting;
(v) drying the composition under heating conditions;
The method is provided.

DETAILED DESCRIPTION The present invention relates to a composition suitable for use in the production of a transdermal delivery patch for administration of a bioactive compound, the composition comprising a tocopherol phosphate compound and a polymeric carrier. The composition or matrix layer can form part of a transdermal delivery matrix patch. It was a surprising discovery that transdermal delivery patches containing this composition or matrix layer can deliver bioactive compounds efficiently.

Tocopherol Phosphate Compound The composition or matrix layer contains a tocopherol phosphate compound.

  Vitamin E exists in eight different forms: four tocopherols and four tocotrienols. All feature a chroman ring with a hydroxyl group that can donate a hydrogen atom to reduce free radicals and a hydrophobic side chain that allows penetration into the biological membrane. Such derivatives of vitamin E may be classified as “hydroxychromans”. Both tocopherols and tocotrienols occur in alpha, beta, gamma and delta forms determined by the number and position of the methyl groups on the chroman ring. Tocotrienols differ from similar tocopherols by the presence of three double bonds in the hydrophobic side chain. Various forms of vitamin E are represented by formula (I).

  In the present invention, any of the four forms of tocopherol may be used. α type is preferred.

The term “phosphate compound” refers to a phosphorylated compound in which a covalent bond is between the oxygen atom of the compound (typically derived from a hydroxyl group) and the phosphorus atom of the phosphate group (PO ₄ ). Formed, and in this context, the compound is an electron transfer agent.

  The phosphoric acid compound may be a phosphoric acid mono-ester, phosphoric acid di-ester, phosphoric acid tri-ester, pyrophosphoric acid mono-ester, pyrophosphoric acid di-ester, or a salt or derivative thereof, or a mixture thereof. Good. The di- and tri-esters may comprise the same or different tocopherols.

  “Salts” include, for example, sodium, magnesium, potassium and calcium salts, metal salts such as alkali or alkaline earth metal salts. Sodium and potassium salts are preferred.

  “Derivatives” include phosphate compounds in which one or more phosphate protons are replaced by substituents. Some non-limiting examples of derivatives include phosphatidyl derivatives in which the phosphate proton is replaced with an amino-alkyl group, sugar derivatives in which the phosphate proton is replaced with a sugar such as glucose.

The term “amino-alkyl group” refers to a group comprising an amino group (—NH ₂ ) and an alkyl group. The term “alkyl” refers to a straight, branched or cyclic hydrocarbon group having from 1 to 8 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, cyclohexyl, heptyl, and octyl. Most preferred are phosphatidylcholine derivatives.

  The phosphoric acid compound of tocopherol is mono- (tocopheryl) phosphate, mono- (tocopheryl) phosphate monosodium salt, mono- (tocopheryl) phosphate disodium salt, mono- (tocopheryl) phosphate monopotassium salt, mono- -(Tocopheryl) phosphate dipotassium salt, di- (tocopheryl) phosphate, di- (tocopheryl) phosphate monosodium salt, di- (tocopheryl) phosphate monopotassium salt, or combinations thereof Also good. These phosphate compounds may be derived from alpha, beta, gamma, or delta forms of tocopherol, or combinations thereof.

  In the case of monophosphate and diphosphate, that is, mono- (tocopheryl) phosphate and di (tocopheryl) phosphate (herein, a mixture of tocopheryl phosphate, or simply “TPM”) The ratio (% w / w) is preferably at least about 2: 1, more preferably from about 4: 1 to about 1: 4, and most preferably from about 6: 4 to about 8: 2. The ratio may be about 2: 1, about 6: 4, or about 8: 2.

  The composition or matrix layer is about 0.01% w / w to about 10% w / w, or about 0.1% w / w to about 5% w / w, about 0.1% w / w to their total amount. About 3% w / w, about 0.1% w / w to about 2% w / w, about 0.1% w / w to about 1% w / w or about 0.1% w / w to about 0.5% w / w tocopherol The phosphoric acid compound may be contained. In some embodiments, the tocopherol phosphate compound is included from about 0.5% w / w to about 1.5% w / w, or about 0.1% w / w, relative to the total amount of the composition or matrix layer. Also good.

Polymer carrier The composition or matrix layer also comprises a polymer carrier.

  The polymer carrier may include natural and synthetic polymers, copolymers or terpolymers.

  Natural polymers include rubber, elastomers, polysaccharides including cellulose, natural resins including back racks and wrinkles.

  Synthetic polymers include acrylate, polyacrylate, polyalkyl acrylate, polyamide, polyester, polycarbonate, polyimide, polystyrene, acrylonitrile butadiene styrene, polyacrylonitrile, polybutadiene, poly (butylene terephthalate), poly (ether sulfone), poly (ether) ketone, Polyethylene, poly (ethylene glycol), poly (ethylene terephthalate), polypropylene, polytetrafluoroethylene, styrene-acrylonitrile resin, poly (trimethylene terephthalate), polyurethane, polyvinyl butyral, polyvinyl chloride, polyvinylidene difluoride, povidone, poly (Vinyl pyrrolidone), polychloroprene, fluoroelastomer, chlorosulfonated rubber, Ipromellose, polyolefin elastomer, polyacrylamide, chlorinated polyethylene, polyethylene sulfone, nylon, liquid crystal polymer, polyethylene terephthalate (PET), polyphenyl sulfone, polyphthalamine polyvinyl alcohol derivative, polyethylene glycol, ethylene vinyl acetate, polymethyl methacrylate, cellulose Derivatives, ethylcellulose, hydroxypropylmethylcellulose, sugar derivatives (rubber), sorbitol and mannitol, silicone oils and silicone oil derivatives, polysiloxanes, amine resistant polysiloxanes, siloxanes and the like.

  Preferred polymeric carriers suitable for use in the compositions or matrix layers of the present invention include acrylates, povidone and siloxanes. Particularly preferred polymer carriers include polyvinylpyrrolidone (eg PVP K90, MW 360,000 Da), polysiloxane, polyalkyl acrylate (eg DuroTak) and polymethyl methacrylate (eg Eudragit E100). In one embodiment, the polymer carrier is polyvinyl pyrrolidone. In another embodiment, the polymer carrier is polymethyl methacrylate.

  The polymeric carrier used in the composition or matrix layer may have sufficient tack to allow the transdermal delivery patch to adhere to the skin. For example, amine resistant polysiloxanes and combinations thereof can be used in the composition or matrix layer. Most preferred is the use of a combination of a moderately sticky polysiloxane and a highly sticky polysiloxane. The polysiloxane may be synthesized from a linear bifunctional oligomer and a branched multifunctional oligomer. The ratio of both types of oligomers is known to determine the physical properties of the polymer. When there are many multifunctional oligomers, cohesion is high and adhesiveness falls. When there are few multifunctional oligomers, adhesiveness is high and agglomeration falls. The high tack should be sticky enough to adhere the transdermal delivery patch to the surface of the skin. Medium tackiness can be useful by providing a softening action to the composition or other components contained in the matrix layer. Silicone oil (eg, dimethicone) can be added to increase the adhesion of the composition.

  The composition or matrix layer is about 20% w / w to about 99% w / w, about 85% w / w to about 98% w / w, about 20% w / w to about 95% w of their total amount. / w, about 30% w / w to about 95% w / w, about 30% w / w to about 80% w / w, or about 55% w / w to about 65% w / w polymer carrier Can do. In some embodiments, the composition or matrix layer is about 85% w / w to about 95% w / w, about 85% w / w to about 98% w / w, or about 90% of their total amount. It may contain from w / w to about 95% w / w polymer carrier.

  In addition, the polymer carrier may contain an inert carrier component, and in order to achieve appropriate flexibility, flexibility, and “tackiness”, for example, it contains an anti-adhesive agent, a tackifier, and the like. Also good.

  Polymers that are originally “sticky” and need an anti-adhesive agent to have the appropriate hardness have no adhesive properties (i.e. low ability to retain solvent when dried) and are well mixed with the polymer An anti-adhesive agent that is a solid (ie, does not crystallize when dried) may be suitable. The selection may be based on the type of polymer. Many surfactants are suitable for use as an anti-adhesive with a polymeric carrier. A more specific example of an anti-adhesive is succinic acid. In certain embodiments, the anti-adhesive agent is present at less than about 1% w / w, up to about 1% w / w, or up to about 5% w / w relative to the total amount of the composition or matrix layer. May be.

  In order to improve the adhesion of the composition or the matrix layer to the surface of the skin, a tackifier (adhesive) may optionally be contained. Tackiness may be controlled by combining adhesives of varying hardness (glass temperature or Tg). Typically, tackifiers are polymers that are not soluble in water and are composed of monomers that partially or wholly contain methacrylic or acrylic alkyl esters. Such polymers include, but are not limited to, acrylic, N-butyl-methacrylic copolymer (Primal N580NF, Japan Acrylic Chemical Company, Ltd.), acrylic methyl, acrylic 2-ethylhexyl copolymer (Nikasol TS-6520, Nippon Carbide Industries Company, Ltd.), polyacrylic acid (Jurymer AC-IOLPH, Nihon Junyaku Company, Ltd), methacrylic copolymer L (Plastoid L50, Rohm Pharma GmbH), and aminoalkyl methacrylate copolymer E (Plastoid E35L, Plastoid E35M, Plastoid E35H, Rohm Pharma GmbH) ). Other non-limiting examples include rosin esters, hydrogenated rosins, dipropylene glycol dibenzoates, and / or mixed hydrocarbons, and acrylic copolymers (eg, Flexbond 150 adhesive, Air Products).

  Plasticizers are additives that increase the plasticity or fluidity of the material to which they are added. Plasticizers are used in the present invention to increase the fluidity of the final product. Suitable plasticizers include phthalates, esters of polycarboxylic acids with medium length linear or branched aliphatic alcohols, acetylated monoglycerides, alkyl citrates, triethyl citrate (TEC), acetyl triethyl citrate ( ATEC), tributyl citrate, (TBC), acetyl tributyl citrate (ATBC), trioctyl citrate (TOC), acetyl trioctyl citrate (ATOC), trihexyl citrate (THC), acetyl trihexyl citrate ( ATHC), butyryl trihexyl citrate (BTHC, trihexyl o-butyryl citrate), trimethyl citrate (TMC), methyl laurate, lauric acid, lauryl lactate, lauryl alcohol, alkylsulfonic acid phenyl ester, diethylene glycol Monoethyl ester, bis (2-ethylhexyl) phthalate (DEHP), diisooctyl phthalate (DIOP), bis (n-butyl) phthalate (DnBP, DBP), diisobutyl phthalate (DIBP), bis (2-ethylhexyl) adipate ( DEHA), dimethyl adipate (DMAD), monomethyl adipate (MMAD), dioctyl adipate (DOA), ethyl oleate, sorbitan monooleate, glycerol monooleate, dibutyl sebacate (DBS), dibutyl maleate (DBM), diisobutyl Maleate (DIBM), benzoate, epoxidized vegetable oil, Tris (tromethamine), N-ethyltoluenesulfonamide (o / pETSA), N- (2-hydroxypropyl) benzenesulfonamide (HP BSA), N- (n- Butyl) Ben Sulfonamide (BBSA-NBBS), tricresyl phosphate (TCP), tributyl phosphate (TBP), triethylene glycol dihexanoate (3G6, 3GH), tetraethylene glycol diheptanoate (4G7), 1, 3 -Including butylene glycol, dipropylene glycol, PEG 400, Span 80, and polyvinyl pyrrolidone. Dibutyl sebacate (DBS), sorbitan monooleate, methyl laurate and lauric acid are preferred plasticizers.

  The inert carrier composition is applied to the composition or matrix layer in an amount of about 0.001% w / w to about 50% w / w, up to about 40% w / w, up to about 30%, based on their total amount. w / w may be present. In one embodiment, the composition or matrix layer contains about 35% w / w of an anti-adhesive agent (such as succinic acid) and a plasticizer (eg, dibutyl sebacate), based on their total amount.

  The amount of polymeric carrier and any inert carrier component present in the composition or matrix layer will depend on the particular bioactive compound being administered. Generally, however, the composition or matrix layer is about 50% w / w to about 99% w / w, about 80% w / w to about 98% w / w, about 90%, based on their total amount. From w / w to about 98% w / w of these ingredients may be included. In one embodiment, the composition or matrix layer may contain about 95% w / w of these components relative to their total amount.

  The term “polymer carrier” is used herein as a generic term for polymer carrier and inert carrier components.

  The composition or matrix layer optionally further comprises one or more excipients (in addition to the inert carrier component).

  One skilled in the art of the present invention may recognize excipients suitable for inclusion in the composition or matrix layer of the present invention. Examples include, but are not limited to, solvents, wettable or gelling agents, preservatives, surfactants, stabilizers, buffers, emollients, colorants, fragrances, and appearance modifiers. It will be appreciated that any excipient suitable for use in pharmaceuticals can be employed in the composition or matrix layer of the present invention. The amount of specific excipients used in the composition or matrix layer of the present invention can also be understood by those skilled in the art.

Bioactive compounds The composition or matrix layer may form part of a transdermal delivery matrix patch. It was a surprising discovery that transdermal delivery patches containing this composition or matrix layer can efficiently contain bioactive compounds.

  The term “bioactive compound” refers to any chemical having a biological effect in humans or animals for medical, therapeutic, cosmetic and veterinary purposes, and drugs, medicinal cosmetics, dietary supplements, and nutrition Includes pharmaceuticals containing agents. It will be appreciated that some bioactive compounds can be classified for more than one of these classifications.

  A wide range of bioactive compounds may be delivered with the transdermal delivery patch of the present invention. Examples are cardiovascular drugs, especially antihypertensives (eg calcium channel blockers or calcium antagonists) and antiarrhythmic drugs; drugs for congestive heart failure; cardiotonic drugs; vasodilators; ACE inhibitors; diuretics; Enzyme inhibitors; cardiac glycosides; phosphodiesterase inhibitors; alpha blockers; beta blockers; sodium channel blockers; potassium channel blockers; beta-adrenergic agonists; platelet inhibitors; angiotensin II antagonists; Coagulant; Thrombolytic agent; Treatment of bleeding; Treatment of anemia; Thrombin inhibitor; Antiparasitic agent; Antibacterial agent; Insulin; Human growth hormone and peptide; Vaccine; Anti-inflammatory agent, especially non-steroidal anti-inflammatory agents (NSAIDs) ) More specifically COX-2 inhibitors; steroidal anti-inflammatory agents; prophylactic anti-inflammatory agents; anti-glaucoma agents; mast cell stabilizers; mydriatics; Drugs that affect the system; allergic rhinitis drugs; alpha-adrenergic drugs; corticosteroids; drugs for chronic obstructive pulmonary disease; xanthine-oxidase inhibitors; anti-arthritic drugs; treatment for gout; Antimycobacterial agents; antifungal agents; antiprotozoal agents; anthelmintic agents, especially antiviral agents for respiratory, herpes, cytomegalovirus, human immunodeficiency virus and hepatitis infection; treatment of leukemia and Kaposi's sarcoma; And opioid pain management agents, including analgesics, opioid receptor agonists, opioid receptor partial agonists, opioid antagonists or mixed agonist-antagonist opioid receptors; tranquilizers; sympathomimetic drugs; adrenergic agonists; Incorporation of substances Or drugs that affect release; anticholinergic drugs; antihemorrhoid therapy; drugs for radiation prevention or treatment or chemotherapy; lipogenesis drugs; fat reduction therapy; anti-obesity peptides; anti-obesity peptides; Obesity drugs; sympathomimetics; treatment for gastric ulcers and inflammation such as proton pump inhibitors; prostaglandins; VEGF inhibitors; antihyperlipidemic agents, especially statins; antipsychotics, antiepileptics and anticonvulsants (Anticonvulsants), psychotropic drugs, stimulants, anxiolytic and hypnotics, drugs that affect the central nervous system (CNS) such as antidepressants; antiparkinsonian drugs; hormones such as sex hormones And their fragments; growth hormone antagonists; gonadotropin release Hormones and their analogs; steroid hormones and their antagonists; selective estrogen modulators; growth factors; antidiabetic drugs such as insulin, insulin fragments, insulin analogs, glucagon-like peptides and hypoglycemic agents; Antihistamines; natural proteins, peptides, oligonucleotides and nucleic acids and analogs, fragments and variants of such compounds; drugs used to treat migraine; pharmaceuticals for asthma; cholinergic antagonists; glucocorticoids Androgen; antiandrogen; adrenocorticoid biosynthesis inhibitor; osteoporosis drug such as bisphosphonate; antithyroid drug; sunscreen, sun protec ant) and filter; cytokine agonist; cytokine antagonist; anticancer agent; anti-Alzheimer drug; HMGCoA reductase inhibitor; fibrate drug; cholesterol absorption inhibitor; HDL cholesterol-elevating agent; triglyceride-reducing agent; anti-aging or anti-wrinkle agent Precursor molecules for hormone production; proteins such as collagen and elastin; antibacterial agents; anti-acne agents; antioxidants; hair treatments and whitening agents; sunscreens, sun protectants and filters; Variants; precursor molecules for hormone production; proteins and their peptides; amino acids; plant extracts such as grape seed extract; DHEA; isoflavones; Nutrients including min, phytosterols and iridoid glycosides, sesquiterpene lactones, terpenes, phenolic glycosides, triterpenes, hydroquinone derivatives, phenylalkanones; antioxidants such as retinol and other retinoids including coenzyme Q10; omega 3 Fatty Acids; Glucosamine; Nucleic Acids, Oligonucleotides, Antisense Drugs; Enzymes; Cytokines; Cytokine Analogs; Cytokine Agonists; Cytokine Antagonists; Immunoglobulins; Antibodies; Antibody Drugs; Gene Therapy; Lipoproteins; Cancer, diabetes, growth disorder, cardiovascular disease, inflammation, immune disease, alopecia, pain, ophthalmic disease, epilepsy, gynecological disease, central nervous system disease, Will Including, but not limited to, low or high molecular weight therapeutics for the treatment or prevention of humans and animals such as viral infections, bacterial infections, parasitic infections, GI diseases, obesity, and blood diseases. Some specific non-limiting examples of suitable bioactive substances include:

Anesthetic:
Benzocaine, chloroprocaine, cocaine, reserpine, guanethidine, cyclomethylcaine, dimethokine / larocaine, propoxycaine, procaine / novocaine, propallacaine, tetracaine / amethocaine; / Includes amino-esters and amino-amide anesthetics such as lignocaine, mepivacaine, piperocaine, prilocaine, ropivacaine, trimecaine, propofol, halothane, enflurane, barbiturate, benzodiazepine, neostigmine and ketamine.

Alkylating agent:
Contains carmustine, cyclophosphamide, ifosfamide, streptozotocin and mechloretamine.

Calcium channel blockers:
Amlodipine, alanidipine, azelnidipine, varnidipine, benidipine, cilnidipine, clevidipine, clonidipine, dalodipine, dexinigurdipine, efonidipine, ernadipine, ergodipine, felodipine, flordipine, flunidipine, iganidipine, esradipine, midipine, m , Nicardipine, nifedipine, nildipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, orladipine, oxodipine, paronidipine, pranidipine, saganidipine, solnidipine, terdipine, thiamdipine, thrombodipine, watanidipine, verapamil, zelopamil, thiapamipil, thiapamipil Including the Rusupiriren and fendiline.

Antiarrhythmic and antianginal drugs:
Includes amiodarone, disopyramide, flecainide acetate, quinidine sulfate, nitroglycerin, ranolazine, amiodarone, isosorbide and alteplase.

Antibacterial, antibiotic and anti-acne agents:
Amoxicillin, ampicillin, azithromycin, venetamine penicillin, bleomycin, benzoyl peroxide, sinoxacin, chloramphenicol, daunorubicin, pricamycin, fluoroquinolone, ciprofloxacin, clarithromycin, clindamycin, clindamycin phosphate ), Clofazimine, chlorohexidine gluconate, cloxacillin, demeclocycline, doxycycline, erythromycin, ethionamide, imipenem, indomethacin, rimocycline, minocycline, nalidixic acid, nitrofurantoin, penicillin, rifampicin, spiramycin sodium, sulfacetamide, sulfacetamide Benzamide, sulfadoxine, sulfamerazine, sulf Acetamide, sulfadiazine, sulfafurazole, sulfamethoxazole, sulfapyridine, tetracycline, cephalexin, cefdinir, triclosan, ofloxacin, vancocin, glyburide, mupirocin, cefprodil, cefuroxime axetil, norfloxacin, isoniazid, lupron, D- Includes penicillamine, levofloxacin, gatifoxacine, and trimethoprim.

Anticancer drugs:
Contains doxorubicin, 6-thioguanine, paclitaxel, docetaxel, camptothecin, megestrol acetate, navelbine, cytarabine, fludarabine, 6-mercaptopurine, 5-fluorouracil, teniposide, vinblastine, vincristine, cisplatin, colchicine, carboplatin, procarbazine and etopside.

Anti-depressant, anti-sperm and anxiolytics:
Alprazolam, amoxapine, bentazepam, bromazepam, chlorazipine, clobazam, clothiazepam, diazepam, lorazepam, flunitrazepam, flurazepam, lormetazepam, medazepam, nitrazepam, zezepam, tezepam ), Trimipramine malate, fluoxetine, ondansetron, midazolam, chlorpromazine, haloperidol, triazolam, clozapine, fluopromazine, fluphenazine decanoate, fluanison, perphenazine, pimozide, prochlorperazine, sulpiride, thioridazine, Paroxetine, citalopram Including bupropion, phenelzine, olanzapine, the divalproex sodium and venlafaxine.

Tricyclic antidepressants:
Includes azothiopine, amitriptyline, famotidine, promethazine, paroxetine, oxcarbazepine and merazapine.

Antidiabetic drugs:
Including acetohexamide, chlorpropamide, glibenclalide, gliclazide, glipizide, metformin, tolazamide, glyburide, glimepiride and tolbutamide.

Antiepileptic drugs:
Bechramid, carbamazepine, gapapentine, tiagabine, vigabatrin, topiramate, clonazepam, ethotoin, methoin, methosuximide, methylphenobarbitone, oxycarbazepine, parameterdione, phenacemide, phenobarbitone, phenytoin, fenceximide, primidone, sultiumphenyto Contains sodium, nilofurantoin monohydrate, gabapentin, lamotrigine, zonisamide, ethosuximide and valproic acid.

Hypnosis / sedation and muscle relaxant:
Zolpidem tartrate, amylobarbitone, barbitone, butobarbitone, pentobarbitone, brotizolam, carbromar, chlordiazepoxide, chlormethiazole, etinamate, meprobamate, metacaron, cyclobenzaprene, cyclobenzaprine, tizanidine, baclofen, butalbital, zopiclone Contains lithium, tubocurarine and phenobarbital.

Antifungal, antiprotozoal and anthelmintics:
Amphotericin, butconazole nitrate, clotrimazole, econazole nitrate, fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate, terconazole, thioconazole and undecenoic acid; Including quinol, decoquinate, diiodohydroxyquinoline, diloxanide furoate, dinitramide, furazolidone, metronidazole, nimorazole, nitrofurazone, ornidazole, terbinafine, clotrimazole, chloroquine, mefloquine, itraconazole, pyrimethamine, praziquantel, quinacrine, and tinidazole .

Antihypertensive and cardiac therapies:
Contains candesartan, hydralazine, clonidine, triamterene, felodipine, gemfibrozil, fenofibrate, nifedical, prazosin, mecamylamine, doxazosin, dobutamine and lexetyl.

Anti-migraine agents:
Dihydroergotamine mesylate, ergotamine tartrate, methysergide maleate, pizotifen malate and sumatriptan succinate.

Antimuscarinic agents:
Contains atropine, benzhexol, biperidene, etopropazine, hyoscyamine, mepenzolate bromide, oxybutynin, oxyphencyclimine and tropicamide.

Antineoplastic agents (or immunosuppressants):
Aminoglutethimide, amsacrine, azathioprine, busulfan, chlorambucil, cyclosporine, dacarbazine, estramustine, etoposide, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitozantrone, procarbazine, tamoxifen citrate, test lactone, tacrolimus Contains mercaptopurine and sirolimus.

Antiparkinsonian:
Contains hypoglycemic agents such as bromocriptine mesylate, levodopa, tolcapone, ropinirole, bromocriptine, sulfonylurea, biguanides, α-glucosidase inhibitors, thiazolidinediones, cabergoline, carbidopa and lisuride maleate.

Antithyroid agents:
Contains carbimazole and propylthiouracil.

Antiviral drugs:
Amantadine, retinovir, cidofovir, acyclovir, famciclovir, ribavirin, amprenavir, indinavir, rimantadine and efavirenz, penciclovir, ganciclovir, vidarabine, abacavir, adefovir, amprenavir, delavirdine, zidanocinbin, zidanocin , Zidovudine, enfuvirtide and interferon.

Cardiotonic drugs:
Amrinone, milrinone, digitoxin, digoxin, enoximone, lanatoside C and medigoxin.

Antihyperlipidemic and hyperlipidemic agents:
Includes fenofibrate, clofibrate, probucol, ezetimibe and torcetrapib.

Anti-inflammatory agents:
Includes meoxicam, triamcinolone, cromolyn, nedocromil, hydroxychloroquine, montelukast, zileuton, zafirlukast and meloxicam.

Antihistamines:
Includes fexofenadine, chloral hydrate, hydroxyzine, promethazine, cetirazine, cimetidine, cyclidine, meclizine, dimenhydrinate, loratadine, nizatidine and promethazine.

Anti-ulcer agent:
Contains omeprazole, lansoprazole, pantoprazole and ranitidine.

Opioid:
Natural opiates that are alkaloids contained in opium poppy resins, such as morphine, codeine and thebaine; semisynthetic opioids produced from opiates such as hydromorphine, hydrocodone, oxycodone, oxymorphine, desomorphin, diacetylmorphine ( Heroin), nicomorphine, dipropanolmorphine, benzylmorphine and ethylmorphine; fully synthetic opioids such as fentanyl, pethidine, methadone, tramadol and dextropropoxyphene; and endogenous opioid peptides naturally produced in the body, such as endol Phen, enkephalin, dynorphin, and endomorphin, etc .; opioid analgesics, opioid receptor agonists, opioid receptor partial agonists, Opioid antagonist or opioid receptor mixed agonist-antagonist; opioid receptor agonist such as morphine, depomorphine, fraction and ruffin, heroin, hydromorphine, oxymorphine, levorphanol, methadone, levomethadyl, meperidine, fentanyl, sufentanil, al Fentanyl, codeine, hydrocodone, oxycodone, and mixtures thereof; opioid receptor antagonists such as naloxone and naltrexone; opioid receptor mixed agonist-antagonists having only opioid agonist / agonist combined activity or partial agonist activity, such as Buprenorphine, nalbuphine, butorphanol, pentazocine, and mixtures of these compounds; partial agoni Opioids with active activity such as ethyl ketocyclazocine; eg phenanthrene opium alkaloids naturally occurring in opium such as codeine, morphine, thebaine and oripavine (active metabolites of thebaine); synthetic derivatives such as diacetylmorphine (heroin) , Dihydrocodeine, hydrocodone, hydromorphine, nicomorphine, desmorphin, ethylmorphine, dipropanoylmorphine, oxycodone, and oxymorphone; synthetic opioids such as anilidepiperidine such as fentanyl, alphamethylfentanyl, alfentanil, sufentanil, remi Fentanyl, carfentanil and offmefentanyl, phenylpiperidine such as pethidine (meperidine), ketobemidone, MPPP Allylprozine, prozine and PEPAP; diphenylpropylamine derivatives such as propoxyphene, dextropropoxyphene, dextromoramide, vegetramide, pyritramide, methadone, dipipanone, levomethadyl acetate (LAAM), diphenoxin, diphenoxylate and loperamide; benzomol Fan derivatives such as benzocine, pentazocine and phenazocine; oripavine derivatives such as buprenorphine, dihydroethorphine and etorphine; morphinan derivatives such as butorphanol, nalbuphine, levorphanol and levomethorphan, and others such as lefetamine, meptazinol, tyridine, tramadol And tapentadol; opioid receptor antagonists such as nalme E down, including the Narukison and naltrexone and the like.

NSAID:
Nonsteroidal anti-inflammatory drugs:
Arylalkanoic acid sub-groups of the class including diclofenac, aceclofenac, acemetacin, alclofenac, bromfenac, etodolac, indomethacin, indomethacin farnesyl, nabumetone, oxametacin, progouritacin, sulindac and tolmetine; aluminoprofen, beoxaprofen, carprofen, Dexuibuprofen, dexketoprofen, fenbufen, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, ketorolac, loxoprofen, miloprofen, naproxen, oxaprozin, pyrprofen, suprofen, tarenflurvir and A class of 2-ants containing thiaprofenic acid Lupropionic acid (profen) sub-group; and N-arylanthranilic acid (phenamic acid) sub-groups including flufenamic acid, meclofenamic acid, mefenamic acid and tolfenamic acid; tromethamine, celecoxib, nepafenac, aspirin, rofecoxib, naproxen , Sulindac, piroxicam, failbutazone, tolmethine, indomethacin, acetaminophen (paracetamol), tramadol and propoxyphene.

Retinoid:
First generation retinoids such as retinol, retinal, tretinoin (retinoic acid, retin-A), isotretinoin and alitretinoin; second generation retinoids such as etretinate and its metabolite acitretin; third generation retinoids such as tazarotene, bexarotene and adapalene including.

Hormones and steroids:
Corticotropin (ACTH), antidiuretic hormone (vasopressin), atrial natriuretic factor (ANF), atrial natriuretic peptide (ANP), beclomethasone, cortisone, scopolamine, dopamine, epinephrine, catecholamine, cholecystokinin, clomiphene Citrate, danazol, dexamethasone, diethylstilbestrol (DES), ethinyl estradiol, fludrocortisone, finasteride, follicle stimulating hormone, gastrin, hydroxyprogesterone, growth hormone, insulin, leptin, luteinizing hormone, medroxyprogesterone acetate, mestranol , Quinestrol, methyltestosterone, nandrolone, norethindrone, norethisterone, norgestrel Estradiol, conjugated estrogens, oxandrolone, oxytocin, prednisone, progesterone, prolactin, prostaglandin, somatostatin, stanozolol, stibesterol, thyroxine, prednisolone phosphate, triamcinolone, mifepristone acetonide, budesonide , Testosterone, testosterocypionate, fluoxymesterone, flutamide, mometasone furoate, cyproterone, fluorometholone, goserelin, leuprolide, calcitonin, halobetasol, hydrocortisol and tibolone.

Statins and derivatives:
Includes atorvastatin, fluvastatin, lovastatin, nystatin, rosuvastatin, pravastatin, orlistat and simvastatin.

stimulant drug:
Contains amphetamine, phentermine, tyramine, ephedrine, metallaminol, phenylephrine, dexamphetamine, dexfenfluramine, fenfluramine, nicotine, caffeine and mazindol.

Vasoconstrictor:
Contains desmopressin.

Vasodilator:
Contains carvedilol, terazosin, phentolamine and menthol.

Anti-Alzheimer drugs:
Contains levetiracetam, lebitiracetam and donepezil.

ACE inhibitors:
Benzapril, enalapril, ramipril, fosinopril sodium, lisinopril, minoxidil, isosorbide, rampril and quinapril.

β-adrenergic receptor antagonists:
Includes atenolol, timolol, pindolol, propanolol hydrochloride, bisoprolol, esmolol, metoprolol succinate, metoprolol and metoprolol tartrate.

Angiotensin II antagonists:
Contains losartan.

Platelet inhibitors:
Contains abciximab, clopidrogel, tirofiban and aspirin.

Alcohol and phenol:
Tramadol, tramadol hydrochloride, allopurinol, calcitriol, cilostazol, saltalol, ursodiol, bromperidol, droperidol, flupentixol decanoate, albuterol, albuterol sulfate, carisoprodol, clobetasol, Contains ropinirole, labetalol, and metocarbamol.

Ketones and esters:
Including amioderone, fluticasone, spironolactone, prednisone, triazodone, desoxymethazone, methyl prednisdone, benzonate nabumetone and buspirone.

Antiemetics:
Contains metoclopramide.

Eye treatment:
Contains dorzolamide, brimonidine, olopatadine, cyclopentrate, pilocarpine and ecothiophosphate.

Anticoagulants and antithrombotic agents:
Contains warfarin, enoxaparin and lepirudin.

Gout treatment:
Contains probenecid and sulfinpyrazone.

Treatment of COPD and asthma:
Contains ipratropium.

Treatment of osteoporosis:
Contains raloxifene, pamidronate and risedronate.

Cosmetic peptides:
Contains acetyl hexapeptide-3, acetylhexapeptide-8, acetyloctapeptide and 1-carnosine.

vaccine:
Proteins, protein subunits and polypeptides; polynucleotides such as DNA and RNA; conjugates; vaccines that include adjuvants such as saponins, virosomes, inorganic and organic adjuvants, such as zostabux, toxoids (inactive toxoid compounds);

Nutritional supplements and medicinal cosmetic active ingredients:
Coenzyme Q10 (or ubiquinone), ubiquinol or resveratrol; carotenoids such as α, β, or γ-carotene, lycopene, lutein, zeaxanthin and astaxanthin; plant nutrients such as lycopene, lutein and zeaxanthin; linoleic acid, conjugated linoleic acid, Unsaturated fatty acids such as, but not limited to, linolenic acid, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA); omega-3 fatty acids and their glycerol; vitamin D (D2, D3 and their derivatives), vitamin E (Α, β, γ, δ-tocopherol or α, β, γ, δ-tocotrienol), vitamin A (retinol, retinal, retinoic acid and derivatives), vitamin K (K1, K2, K3 and derivatives thereof) Including Fat-soluble vitamin, caprylic acid / capric triglyceride, folic acid, iron, niacin, glyceryl linoleate, omega-6 fatty acid, vitamin F, selenium, cyanocobalamin, aloe vera, beta glucan, bisabolol, tea (green tea) extract, caprylic acid / Capric acid triglyceride, Clover (Gautz cola) extract, cetearyl olive, chlorophyll, citrus sinensis (orange) oil, cocoylproline, dicapryl ether, lauriminodipropionate tocopheryl phosphate disodium (vitamin E phosphate), glycerin , Glyceryl oleate, glycyrrhiza grabra (licorice) root extract, Hamelis virginia (witch hazel) extract, lactic acid, lecithin, Lutein, Macadamia Integrifolia (Macadamia) Seed Oil, Matricari Akamomira (Camomile) Extract, Oenothera biennis (Evening Primrose) Oil, Orea europaea (Olive) Leaf Extract, Rice Bran Oil Persia gratissima (avocado) oil, Polygonum multiflorum extract, Pomegranate sterol, Resveratrol, Rosae grand terrier (rose hip) oil, Santarum spicatum (Sandalwood) ) Oil, titanium dioxide, folic acid, glycerin, glyceryl linoleate (omega 6 fatty acid, vitamin F), vitamin A palmitate, Vitis vinifera (grape seed) oil, halobetasol, adenosine, adenosine triphosphate, alpha hydroxy acid, allantoin, hyaluronic acid and derivatives, isoltrol, tranexamic acid, glycolic acid, arginine, ascorbyl glucosamine, ascorbyl palmitate, Salicylic acid, carnosic acid, alpha lipoic acid, gamma linolenic acid (GLA), panthenol, retinyl propionate, retinyl palmitate, furfuryl adenine, retinal dehydride, copper peptide, idebenone, dimethylaminoethanol (DMAE), niacin Amide, β-glucan, palmitoyl pentapeptide-4, palmitoyl oligopeptide / tetrapeptide-7, Tocin, ceramide, phenylalanine, glucuronolactone, L-carnitine, hydroxylapatite, palmitoyl tripeptide-3, forskolin, zinc oxide, α-bisabolol, eugenol, silybin, soy isoflavone, aucbin, catalpol , Pseudoguaianolide from arnica chamissonis, salicylates such as rosmarinic acid, rosmanol, salicin, saligenin and salicylic acid, taxasterol, taxaxelol, Ceramide, arbutin, gingerol, shagaol (Shagaol), hypercin, elastin, collagen and peptides thereof.

  Particularly preferred bioactive compounds are alprazolam, donepazil, rispiredone, lorazepam, nicotine, lidocaine, diclofenac, felodipine, insulin, ketoralac, prilocaine, halobetasol, hydrocortisol, opioids such as oxycodone or dihydrohydroxycodeinone (oxycodone base) )including. Pharmaceutically, nutraceutical or medicinal cosmetically acceptable derivatives of bioactive compounds are within the scope of the present invention.

  The term “pharmaceutically, nutraceutical or pharmaceutically cosmetically acceptable derivative” means a pharmaceutically, nutraceutical or cosmetically acceptable salt, ester, salt of such ester, ether, or Including, but not limited to, any other derivative, including prodrugs and metabolites, which are described herein upon administration to a subject (eg, a patient, human or mammal) as appropriate. It makes it possible to provide bioactive compounds like others directly or indirectly.

  As used herein, the term “pharmaceutical, nutraceutical or medicinal cosmetically acceptable salt” is within the scope of sound medical judgment, excessive toxicity, These salts are suitable for use in contact with human and lower animal tissues without irritation, allergic reactions, and balanced with a reasonable profit / loss ratio. Pharmaceutically, nutraceutical or medicated cosmetically acceptable salts are well known in the art. For example, S.M. M.M. Berge et al. Pharmaceutical Sciences, 66: 1-19, 1977, describes in detail pharmaceutically, nutraceutical or medicinal cosmetically acceptable salts. Pharmaceutically, nutraceutical or pharmaceutically cosmetically acceptable salt-added non-toxic acids are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or acetic acid, A salt of an amino group formed with an organic acid such as oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by use of other methods used in the art such as ion exchange is there. Other pharmaceutically acceptable salts are adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulphate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate , Ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulphate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nito Oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate , Undecanoate, salt of valerate, etc. Exemplary alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. In addition, pharmaceutically acceptable salts use non-toxic ammonium, quaternary ammonium, and counterions such as halides, hydroxides, carboxylates, sulfates, nitrates, lower alkyl sulfonates, and aryl sulfone sulfonates as needed. An amine cation formed.

  The term “pharmaceutical, nutraceutical or medicinal cosmetically acceptable ester” refers to an ester that is hydrolyzed in vivo and that is easily degraded in the human body to release the parent compound or salt thereof. including. Suitable ester groups include pharmaceutically, nutraceutical or pharmaceutically cosmetically acceptable aliphatic carboxylic acids, particularly those derived from alkanoic acids, alkenoic acids, cycloalkanoic acids and alkanedioic acids, and each The alkyl or alkenyl moiety of preferably has no less than 6 carbon atoms. Examples of specific esters include formate, acetate, propionate, butyrate, acrylate and ethyl succinate.

  As used herein, the term “pharmaceutical, nutraceutical or medicinal cosmetically acceptable prodrug” refers to excessive toxicity, irritation within the scope of sound medical judgment. Of the compounds of the present invention as well as being suitable for use in contact with the tissues of the subject with allergic reactions, etc., balanced with a reasonable profit / loss ratio, and effective for their intended use , If possible, refers to their prodrugs of bioactive compounds in zwitterionic form. The term “prodrug” refers to compounds that are readily altered in vivo to yield the parent compound of the formulation, for example, by hydrolysis in blood. A thorough discussion Higuchi and V. Stella, Pro-drugs as Novel Delivery System, A.M. C. S. Symposium Series Vol. 14, and Edward B. Roche, ed. , Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987.

  The present invention is further not limited to administration of only one bioactive compound, but two or more bioactive compounds or other therapeutic compounds may be included in the composition or matrix layer.

  The bioactive compound may be present in a therapeutically effective amount, that is, an amount necessary to achieve the desired therapeutic effect. Typically, the bioactive compound is about 0.1% w / w to about 30% w / w, up to about 20% w / w, up to about 10% relative to the total amount of the composition or matrix layer. % w / w may exist. In one embodiment, the bioactive compound may be present from about 3.0% w / w to about 15.0% w / w based on the total amount of the composition or matrix layer.

  The ratio of bioactive compound: TP (% w / w) may be from about 5: 5 to about 5: 0.5, most preferably about 5: 1. The ratio of polymeric carrier: (bioactive compound and TP) may be from about 1: 1 to about 3: 1, and is preferably from about 7: 6 to about 7: 3.

Preparation of transdermal delivery patch The composition or matrix layer may form part of a transdermal delivery patch. The transdermal delivery patch may be prepared by various techniques.

  One technique is the combination of the polymer carrier and any inert carrier component such as anti-adhesive and / or plasticizer with a suitable solvent (eg 50% water 50% ethanol). This is combined with a dispersion containing the tocopherol phosphate compound and the bioactive compound and stirred until completely uniform. In one embodiment, the composition may be placed in a suitable mold and allowed to dry. In a preferred method, the composition may be dried by heating up to 90 ° C., preferably 0.5-24 hours. However, formulation and / or drying can be performed within a temperature range of about 30 ° C to about 90 ° C. It has been found that better bioactive compound delivery occurs when formulated and / or dried at a temperature of about 75 ° C. In another embodiment, the composition may be flowed over a surface (such as a roller) and dried under heated conditions.

  The composition comprising the tocopherol phosphate compound and the polymer carrier may be a matrix layer. The matrix layer may be a solid or semi-solid layer.

  The transdermal delivery patch typically can have a backing layer. The backing layer functions as a support or basis for the composition or matrix layer. When using a mold to form a transdermal delivery patch, the backing layer may be placed in the mold prior to the addition of the composition or matrix layer.

  Thus, the composition or matrix layer essentially has two surfaces, a first surface and a second surface behind it, the first surface being in contact with the backing layer, Is adapted to contact the subject's skin. The subject may be a human or an animal.

  Preferably, the backing layer is occlusive or occlusive to protect the composition or matrix layer from the outside environment. However, a non-occlusive backing layer may be used as long as the packaging of the transdermal delivery patch is completely closed to prevent degradation of the composition or matrix layer. An occlusive backing layer is preferred.

  The backing layer can be of any thickness, but a typical thickness is from about 0.0005 inches to about 0.01 inches.

  The transdermal delivery patch further has a liner that is a removable protective or impermeable layer, which is not essential, but is “non-sticky” so that it does not stick to the composition or matrix layer. It is. The liner, also called a release liner, protects the transdermal delivery patch during storage. During use, the release liner is removed.

  The liner may be formed of the same material as the backing layer, but metal foil, Mylar®, polyethylene terephthalate, siliconized polyester, fumed silica in silicone rubber, polytretrafluoroethylene, cellophane, silicone Paper, aluminized paper, polyvinyl chloride film, ester, polyester terephthalate, composite foil or film containing polyester or aluminized polyester, polytetrafluoroethylene, polyether block amide copolymer, polyethylene methyl methacrylate block copolymer, polyurethane, polyvinylidene Chloride, nylon, silicone elastomer, rubber-based polyisobutylene, styrene, styrene butadiene, and styrene isoprene copolymers Polyethylene, it may be polypropylene.

  The thickness of the release liner varies, but a typical thickness is about 0.01 mm to about 2 mm.

  The transdermal delivery patch may have an adhesive layer. The adhesive layer may be in addition to the composition or matrix layer, or may be included too much outside of the backing layer, the backing layer extending beyond the edges of the composition or matrix layer. Useful polymer adhesives for transdermal patches include polyacrylate polymers, rubber-based adhesives, and polysiloxane adhesives. These types of materials are described in Van Norstrand (The Handbook of Pressure Sensitive Adhesive Technology Second Edition 1989), along with others, which is hereby incorporated by reference. Examples of commercially available adhesives include, but are not limited to, polyacrylate adhesives such as DUROTAK® from National Starch and Chemical Corporation, Bridgewater, NJ and GELVA-MULTIPOLYMER SOLUTION® from Cytek Surface Specialties, Smyrna, GA Is mentioned.

Advantages It is a surprising discovery that bioactive compounds can be efficiently administered using transdermal delivery patches having a composition or matrix layer containing a phosphate compound of tocopherol and a polymeric carrier.

  Examples of means for transdermal delivery include topical creams and gels, and skin patches.

  Creams and gels are difficult to comply with and dose control, and are considered annoying and undesirable for patients.

  Skin patches come in various forms such as reservoir patches and matrix patches. The patch may be single layer or multiple layers. The reservoir patch essentially has a liquid or gel compartment containing a drug solution or suspension separated by a membrane and a layer of adhesive. In the matrix patch, the drug is present in a semi-solid or solid layer, which may or may not contain an adhesive material.

  Reservoir patches overcome some of the disadvantages of topical creams and gels, but drug delivery is often not uniform and there is a risk of holes in the reservoir. A further problem relates to the delivery of prescription drugs that are dependent and can be abused. Gels, creams, and reservoir patches have limited barriers to drug extraction, but if not included in the composition or matrix layer, drug extraction is difficult, if not impossible. is there.

  Delivery of the active compound orally or by injection results in a non-linear delivery profile. Transdermal delivery provides a non-invasive means that can provide sustained steady state delivery.

  Without being bound by theory, it is believed that the presence of the tocopherol phosphate compound promotes skin penetration of the bioactive compound. It has also been found that the composition or matrix layer cannot be formulated satisfactorily without the use of a tocopherol phosphate compound. It has also been found that the presence of a tocopherol phosphate compound has the function of reducing skin irritation that can be caused by many bioactive compounds.

  The following embodiments may be described with reference to the accompanying drawings.

FIG. 1 is a schematic view of a transdermal delivery patch of one embodiment of the present invention.

FIG. 2 is a graph comparing the delivery of oxycodone using transdermal delivery patches of the present invention prepared with various drying schedules.

FIG. 3 is a graph comparing the delivery of oxycodone using a transdermal delivery patch of the present invention with or without an adhesive layer.

FIG. 4 is a graph comparing the delivery of oxycodone using a transdermal delivery patch of the present invention with or without an occlusive backing layer.

It is a graph which shows the result of the pharmacokinetic test implemented after application of the transdermal delivery patch of this invention.

FIG. 6 is a graph showing the results of a pharmacodynamic test performed after application of the transdermal delivery patch of the present invention.

FIG. 7 is a graph comparing oxycodone delivery using transdermal delivery patches of the present invention containing various plasticizers.

FIG. 8 is a graph comparing oxycodone delivery using transdermal delivery patches of the present invention containing various plasticizers and polymer carriers.

FIG. 9 is a graph showing the mean change in blood glucose after application of the transdermal delivery patch of the present invention to each animal.

FIG. 10 is a graph showing the area under the curve of the graph of FIG.

FIG. 11 is a graph comparing diclofenac deposition in the skin for two diclofenac transdermal delivery patches.

FIG. 12 is a graph comparing diclofenac deposition in the skin for two diclofenac transdermal delivery patches.

FIG. 13 is a graph comparing lidocaine penetration in two lidocaine transdermal delivery patches.

EXAMPLES Various embodiments / aspects of the invention are described with reference to the following non-limiting examples.

Small scale laboratory production The above components were dissolved in a solvent solution (acetone: isopropanol: ethyl alcohol 60: 6.6: 33.5 by weight).

  The resulting solution was poured into individual casts (with an appropriate backing layer) at room temperature and the solvent was evaporated at 75 ° C. for 1 hour.

Large scale production Each component can be combined at an appropriate temperature to create a uniform molten mass. The molten mass is allowed to flow and solidify on a cooling surface (eg, a rotating mill with an appropriate backing layer or sheet). Individual delivery patches of various sizes can be cut out.

  In both methods, the composition or matrix layer is relatively thin, but the thickness of the composition or matrix layer can vary depending on the properties for which the transdermal delivery patch is required. FIG. 1 shows an example of a transdermal delivery patch of one embodiment of the present invention.

Example 2: Other methods of transdermal delivery patch production Eudragit E100 granules, dibutyl sebacate, 20% w / w solid mixture of succinic acid (components other than TPM and oxycodone in the composition or matrix layer are polymer carriers) 6: 4 ratio of mono- (tocopheryl) phosphate and di- (tocopheryl) phosphate combination; and oxycodone base with 60: 6.6: 33.4 acetone / isopropyl alcohol / ethyl alcohol A transdermal delivery patch was constructed by dissolving in. The mixture was transferred to a 6 cm ² aluminum cast lined with a polyester backing (1.66 mil, 3M Scotchpak ^™ , 3M, MN) and the solvent was allowed to evaporate at 45 ° C. overnight or at 75 ° C. for 1.5 hours. If an adhesive was used, the adhesive was DuroTak, in which case succinic acid was omitted from the formulation.

Example 3: Drying temperature comparison test An oxycodone transdermal delivery patch was made according to Example 1 (small scale) to test the difference between two different heating regimes. The transdermal delivery patch was adhered to full thickness human skin applied to a Franz cell with PBS as receiving solution. Time points were taken at 18, 22, 24, 42, 44, 68 and 75 hours, and the receiving solution was tested by HPLC to determine the concentration of oxycodone that passed through the skin.

  The results described in FIG. 2 show that transdermal delivery patches made at higher drying temperatures have increased transdermal delivery capabilities compared to transdermal delivery patches made at lower temperatures.

Example 4: Comparative test to determine the effect of an external adhesive layer As in Example 3, a transdermal delivery patch was made and the receiving solution was at time points of 0.5, 1, 3, 4, and 20 hours. Tested.

  The results of this comparison described in FIG. 3 show that the use of a transdermal delivery patch that includes an adhesive layer is more transdermal as compared to a transdermal delivery patch that is formulated to be adhesive per se. Clearly shows a decline.

Example 5: Comparative test with and without an occlusive backing layer A transdermal delivery patch was made as in Examples 3 and 4, and the receiving solution was 1, 2, 3, 4 and 5 hours time. Tested with points.

  The results described in FIG. 4 demonstrate that transdermal penetration of oxycodone is increased when an occlusive backing layer is used with the patch compared to a patch without an adhesive backing layer.

Example 6: Pharmacokinetic study This example compares plasma PK parameters using Patch Nos, 1, 2, 4, 5 of Example 2.

A transdermal delivery patch was cut from a polyester backing and a 6x7 cm Tegaderm HP ^™ (3M, MN) with or without a backing layer on a shaved and washed back of a 10-12 week old male Sprague-Dawley rat It was stretched using an adhesive dressing. Tegaderm helps to fix the occlusive backing layer or, if there is no such backing layer, fixes the transdermal delivery patch itself.

  The day after the transdermal delivery patch was applied to the shaved portion, the tip of the tail was cut 1 mm at a specific time, and a blood sample was collected.

Quantified PK parameter Cmax: the maximum plasma oxycodone concentration measured.
AUC0-4: Area under the curve of 0-4 hours (experiment duration is 4 hours). A measure of the amount of drug delivered.

  FIG. 5 and the table below show that various dosage forms of the transdermal delivery patch of the present invention enable efficient delivery of oxycodone to rats as shown in the pharmacokinetic data. .

Example 7: Pharmacodynamic test Patch Nos. Rats were treated as in Example 6 using 1, 3 and 5.

The day after the transdermal delivery patch was applied to the shaved area, pain inhibition of the hind limbs was evaluated with a plantar analgesic meter having an IR source corrected to 190 Mu / cm ² .

PD parameters evaluated Maximum: The maximum time it took for a rat to release its leg in response to a thermal stimulus. The higher the value, the longer it took for the rat to react, indicating deeper induction of analgesia by oxycodone.
AUC: A measure of total analgesic during the measurement time measured by the area under the curve from 0 to 4 hours, useful for comparing responses to different treatments.

  The baseline response time is shown in FIG. 6 with t = (− 0.5h) and t = 0.

  The results listed in the table below and FIG. 6 show that analgesics were efficiently administered to rats using various compositions of the present invention.

Example 8: Alternative Plasticizer The following formulation was prepared as described in Example 2. Formulation 1 was placed on a die and Formulation 2 was placed on a plate. The percentages below reflect the composition when the patch is dry.

  The transdermal delivery patch was adhered to full thickness human skin applied to a Franz cell with PBS as receiving solution. Time points were taken at 1, 2 and 4 hours and the receiving solution was tested by HPLC to determine the concentration of oxycodone that passed through the skin.

  The results are described in FIG. 7 and show that oxycodone delivery can be achieved using alternative plasticizers.

Example 9
Alternative Polymer Carrier The following formulation was prepared as in Example 1, but the composition was placed on a flat surface or plate rather than a die.

  The transdermal delivery patch was adhered to full thickness human skin applied to a Franz cell with PBS as receiving solution. Time points were taken at 1, 2 and 4 hours and the receiving solution was tested by HPLC to determine the concentration of oxycodone that passed through the skin.

  The results are described in FIG. 8 and show that oxycodone is delivered transdermally using an alternative polymer carrier.

Example 10: Investigation of Pharmacodynamics of Insulin Formulated in Transdermal Delivery Patch Four transdermal delivery patches of the present invention were tested against a positive control gel.

  The table below shows the composition of the composition or matrix layer in four transdermal delivery patches. Polyvinyl pyrrolidone has been found to provide a composition or matrix layer with sufficient “stickiness” to avoid the need to add an inert carrier component. The dry weight of each transdermal delivery patch was 60 mg.

  The composition or matrix layer components were dissolved in a solvent solution (50% water, 50% ethanol). The resulting solution was poured into casts (with an appropriate backing layer) at room temperature and the solvent was evaporated at 75 ° C. for 1.5 hours.

  A 300 mg gel was used as a positive control, which contained 2.25 mg / ml insulin, TPM (2: 1) 2% TPM, ethanol 30%, Carpobol 934 1% carpobol 934 in water, pH = 4.7. It has been adjusted.

Experimental Design This experiment was to test the transdermal delivery patch of the present invention compared to a gel. In this design, each animal received 4 of 5 treatments during the course of the experiment. These animals were male and were 10-12 weeks old. Each treatment group had 11 animals. All animals weighed over 300 g and had a circulating glucose concentration of> 10 mmol / L in the fasted state (mean fasting glucose concentration of 21.37 ± 0.85 mmol / L). The experimental endpoint was blood glucose level during the 5-hour insulin tolerance test and was performed as follows.

Streptozotocin administration Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ) 50 mg / kg (Sigma Chemicals) dissolved in sodium citrate buffer (0.1 mol / L, pH 4.5) immediately before use. Rats whose blood glucose level exceeded 16 mmol / L 24 hours after STZ injection were used as diabetic rats in the experiment. In all groups, blood glucose was measured by obtaining blood from the tip of the tail. The animals were used for experiments 5 days after STZ administration.

Treatment Procedure 24 hours prior to application of the gel and transdermal delivery patch, the animals were anesthetized and 30 cm ² of the back was shaved so as not to damage the formulation which would increase the absorption of the formulation. The gel was applied at a dose of 12 mg / cm ² to shaving portion. The transdermal delivery patch was adhered to the shaved portion and protected with a Tegaderm dressing. An insulin resistance test was performed 24 hours after shaving. After each treatment, the animals were allowed to recover for 3 days before the next treatment.

ITT (insulin tolerance test)
Animals were fasted for 2 hours before application of insulin or control formulation. Blood samples were collected from the tail at 0, 30, 60, 90, 120, 180, 240 and 300 minutes after application of the gel and transdermal delivery patch. Blood glucose levels were determined using a glucose stick (AccuChek, Roche Diagnostics).

Results The gel and transdermal delivery patch caused a significant decrease in blood glucose concentration in diabetic rats (FIGS. 9 and 10). Blood glucose dropped significantly from the book values 30 minutes after application (p <0.05) and remained low throughout the study period. As shown by the area under the curve, there was no statistically significant difference in blood glucose reduction between the patch and gel used in this study (FIG. 10). Although the transdermal delivery patch appears to be effective for delivery of insulin, the transdermal delivery patch provides many of the advantages described herein compared to gels and other delivery methods.

Example 11: Diclofenac Transdermal Delivery Patch A diclofenac diethylamine transdermal delivery patch was made with the following composition.

The surface area of the diclofenac diethylamine transdermal delivery patch was 120 cm ² .

Production method
The components listed in the table above were dissolved in 30 ml isopropanol: acetone mixture (1: 1) at 45 ° C. The mixture was placed on a 3M scotch pack and dried at 75 ° C. for 90 minutes.

In vitro test (dispersion)
Transdermal delivery patches were cut into discs (7 cm ² ) and placed on rat skin. The receiving solution was 12 ml and the effective surface area was equivalent to about 1.76 cm ² for the skin. After the experiment, the skin was collected, the surface was washed, and extracted with 10 ml of solvent.

Results The results are shown in FIGS.

Example 12: Lidocaine Transdermal Delivery Patch A lidocaine transdermal delivery patch was made with the following composition.

The surface area of the lidocaine transdermal delivery patch was 120 cm ² .

Production method
The components listed in the table above were dissolved in 30 ml isopropanol: acetone mixture (1: 1) at 45 ° C. The mixture was placed on a 3M scotch pack and dried at 75 ° C. for 90 minutes.

In vitro test (dispersion)
Release liner delivery patches were cut into discs (7 cm ² ) and placed on rat skin. The receiving solution was 12 ml and the effective surface area was equivalent to about 1.76 cm ² for the skin. After the experiment, the skin was collected, the surface was washed, and extracted with 10 ml of solvent.
In-vitro testing (Diffusion)

Results The results are shown in FIG.

  In this specification, unless the context requires otherwise, the terms "comprise", "comprises", and "comprising" are "include", "include" ( includes "and" including ", that is, where the invention is described or defined as specific features, various embodiments of the same invention may also include additional features. But you can.

  Although the invention has been described by way of example and with reference to possible embodiments thereof, it is to be understood that modifications or improvements may be made without departing from the scope of the invention.

Accordingly, a first aspect of the invention provides a matrix layer for the production of a transdermal delivery patch for administration of a bioactive compound, the matrix layer comprising a mono-tocopheryl phosphate compound and a di-tocopheryl phosphorus. A mixture of acid compounds as well as a polymer carrier, the amount of the polymer carrier being in the range of about 30% w / w to about 95% w / w.

A third aspect of the present invention is a method of preparing a transdermal delivery patch for administration of a bioactive agent, comprising:
(i) combining the polymer carrier and any inert single component with a suitable solvent;
(ii) combining a dispersion containing a bioactive compound and a mixture of mono-tocopheryl phosphate compound and di-tocopheryl phosphate compound with the product of (i);
(iii) stirring the product of (ii) until completely uniform;
(iv) placing the composition of (iii) on the surface of a suitable mold or casting;
(v) drying the composition under heating conditions;
The method is provided.

Tocopheryl phosphate compound The composition or matrix layer contains a mixture of a mono-tocopheryl phosphate compound and a di-tocopheryl phosphate compound .

The mono-tocopheryl phosphate compound includes mono- (tocopheryl) phosphate, mono- (tocopheryl) phosphate monosodium salt, mono- (tocopheryl) phosphate disodium salt, mono- (tocopheryl) phosphate monopotassium salt. , And mono- (tocopheryl) phosphate dipotassium salt, and the di-tocopheryl phosphate compound is di- (tocopheryl) phosphate, di- (tocopheryl) phosphate monosodium salts, and di - (tocopheryl) may be selected from the group consisting of phosphoric acid monopotassium salt. These phosphate compounds may be derived from alpha, beta, gamma, or delta forms of tocopherol, or combinations thereof.

In the case of monophosphate and diphosphate, that is, mono- (tocopheryl) phosphate and di (tocopheryl) phosphate (herein, a mixture of tocopheryl phosphate, or simply “TPM”) The ratio (% w / w) is at least in the range of about 2: 1, about 4: 1 to about 1: 4, about 6: 4 to about 8: 2. The ratio may be about 2: 1, about 6: 4, or about 8: 2.

The mixture of mono-tocopheryl phosphate compound and di-tocopheryl phosphate compound is in the range of about 0.01% w / w to about 10% w / w, or about, relative to the total amount of the composition or matrix layer. in the range of 0.1% w / w to about 5% w / w, in the range of about 0.1% w / w to about 3% w / w, in the range of about 0.1% w / w to about 2% w / w, It may be present in the range of about 0.1% w / w to about 1% w / w or in the range of about 0.1% w / w to about 0.5% w / w. In some embodiments, the mixture of mono-tocopheryl phosphate compound and di-tocopheryl phosphate compound is about 0.5% w / w to about 1.5% w / w relative to the total amount of the composition or matrix layer. in the range of w, or may be contained in the range of about 0.1% w / w.

The polymeric carrier may be in the range of about 30% w / w to about 95% w / w of the total amount of the composition or matrix layer, in the range of about 30% w / w to about 80% w / w, or about It may be contained within the range of 55% w / w to about 65% w / w .

Inert carrier composition, the total amount of the composition or matrix layer in the range of about 0.001% w / w to about 50% w / w, from about 0.001% w / w to about 40% w / w It may be present within a range of about 0.001% w / w to about 30% w / w. In one embodiment, the composition or matrix layer contains about 35% w / w of an anti-adhesive agent (such as succinic acid) and a plasticizer (eg, dibutyl sebacate), based on their total amount.

The amount of polymeric carrier and any inert carrier component present in the composition or matrix layer will depend on the particular bioactive compound being administered. Generally, however, these compounds are present in the range of about 50% w / w to about 99% w / w, about 80% w / w to about 98% w / w, relative to the total amount of the composition or matrix layer. in the range of w, it may be contained in the range of about 90% w / w to about 98% w / w. In one embodiment, the composition or matrix layer may contain about 95% w / w of these components relative to their total amount.

The bioactive compound may be present in a therapeutically effective amount, that is, an amount necessary to achieve the desired therapeutic effect. Typically, the biologically active compound, based on the total amount of the composition or matrix layer in the range of about 0.1% w / w to about 30% w / w, about 0.1% w / w to about 20% It may be present in the range of about 0.1% w / w to about 10% w / w within the w / w range . In one embodiment, the bioactive compound may be present from about 3.0% w / w to about 15.0% w / w based on the total amount of the composition or matrix layer.

The ratio of bioactive compound: TP (% w / w) may be in the range of about 5: 5 to about 5: 0.5, most preferably about 5: 1. The ratio of polymer carrier: (bioactive compound and TP) may be in the range of about 1: 1 to about 3: 1, and is preferably in the range of about 7: 6 to about 7: 3.

One technique is the combination of the polymer carrier and any inert carrier component such as anti-adhesive and / or plasticizer with a suitable solvent (eg 50% water 50% ethanol). This is combined with a mixture of mono-tocopheryl phosphate compound and di-tocopheryl phosphate compound and a dispersion containing the bioactive compound and stirred until complete homogeneity. In one embodiment, the composition may be placed in a suitable mold and allowed to dry. In a preferred method, the composition may be dried by heating up to 90 ° C., preferably 0.5-24 hours. However, formulation and / or drying can be performed within a temperature range of about 30 ° C to about 90 ° C. It has been found that better bioactive compound delivery occurs when formulated and / or dried at a temperature of about 75 ° C. In another embodiment, the composition may be flowed over a surface (such as a roller) and dried under heated conditions.

The composition comprising a mixture of the mono-tocopheryl phosphate compound and di-tocopheryl phosphate compound and a polymer carrier is suitable for use as a matrix layer . The matrix layer may be a solid or semi-solid layer.

Pros
The bioactive compound can be efficiently administered using a transdermal delivery patch having a composition or matrix layer containing a mixture of a mono-tocopheryl phosphate compound and a di-tocopheryl phosphate compound and a polymeric carrier Is a phenomenal discovery.

Without being bound by theory, it is believed that the presence of a mixture of mono-tocopheryl phosphate compound and di-tocopheryl phosphate compound promotes skin penetration of bioactive compounds. It has also been found that the composition or matrix layer cannot be formulated satisfactorily without the use of a mixture of mono-tocopheryl phosphate compound and di-tocopheryl phosphate compound . It has also been found that the presence of a tocopherol phosphate compound has the function of reducing skin irritation that can be caused by many bioactive compounds.

Claims (45)

  A composition suitable for use in a transdermal delivery patch for administration of a bioactive compound, the composition comprising a tocopherol phosphate compound and a polymeric carrier.   The composition of claim 1, wherein the compound is a matrix layer.   The tocopherol phosphate compound is mono- (tocopheryl) phosphate, mono- (tocopheryl) phosphate monosodium salt, mono- (tocopheryl) phosphate disodium salt, mono- (tocopheryl) phosphate monopotassium salt, mono- Selected from the group consisting of-(tocopheryl) phosphate dipotassium salt, di- (tocopheryl) phosphate, di- (tocopheryl) phosphate monosodium salt, di- (tocopheryl) phosphate monopotassium salt, or combinations thereof The composition according to claim 1 or 2.   4. The composition of claim 3, wherein the tocopherol phosphate compound is a combination of mono- (tocopheryl) phosphate and di- (tocopheryl) phosphate.   The ratio (% w / w) of the combination of mono- (tocopheryl) phosphate and di- (tocopheryl) phosphate is 2: 1 or more, about 4: 1 to about 1: 4, about 6: 4 to about 8 5. The composition of claim 4, wherein the composition is about 2: 2, about 2: 1, about 6: 4, or about 8: 2.   The amount of phosphate compound of the tocopherol is about 0.01% w / w to about 10% w / w, or about 0.1% w / w to about 5% w / w, about 0.1, based on the total amount of the composition. % w / w to about 3% w / w, about 0.1% w / w to about 2% w / w, about 0.1% w / w to about 1% w / w or about 0.1% w / w to about 0.5% The composition according to any one of claims 1 to 5, which is w / w.   7. The composition of claim 6, wherein the amount of the tocopherol phosphate compound is about 0.5% w / w to about 1.5% w / w, or about 0.1% w / w, relative to the total amount of the composition. object.   8. The composition of any one of claims 1-7, wherein the polymeric carrier contains a natural or synthetic polymer, copolymer, terpolymer, or combinations thereof.   The natural polymer is selected from the group consisting of rubbers, elastomers, polysaccharides including cellulose, back racks and natural resins including wrinkles; the synthetic polymer is an acrylate, polyacrylate, polyalkyl acrylate, polyamide, polyester, polycarbonate, Polyimide, polystyrene, acrylonitrile butadiene styrene, polyacrylonitrile, polybutadiene, poly (butylene terephthalate), poly (ether sulfone), poly (ether) ketone, polyethylene, poly (ethylene glycol), poly (ethylene terephthalate), polypropylene, polytetrafluoro Ethylene, styrene-acrylonitrile resin, poly (trimethylene terephthalate), polyurethane, polyvinyl butyral, polyvinyl chloride, polyvinyl chloride Redene difluoride, povidone, poly (vinyl pyrrolidone), polychloroprene, fluoroelastomer, chloro-sulfonated rubber, hypromellose, polyolefin elastomer, polyacrylamide, chlorinated polyethylene, polyethylene sulfone, nylon, liquid crystal polymer, polyethylene terephthalate (PET), polyphenylsulfone, polyphthalamine polyvinyl alcohol derivatives, polyethylene glycol, ethylene vinyl acetate, polymethyl methacrylate, cellulose derivatives, ethyl cellulose, hydroxypropyl methyl cellulose, sugar derivatives (rubber), sorbitol and mannitol, silicone oil and silicone oil Selected from the group consisting of derivatives, polysiloxanes, amine resistant polysiloxanes, and siloxanes. It is the composition of claim 8.   10. Composition according to any one of the preceding claims, wherein the polymer carrier is selected from acrylates, povidone, siloxanes, polyvinylpyrrolidone, polysiloxanes, amine resistant polysiloxanes, polyalkyl acrylates and polymethyl methacrylates. .   The amount of the polymer carrier is about 20% w / w to about 99% w / w, about 85% w / w to about 98% w / w, about 20% w / w, based on the total amount of the composition. ~ About 95% w / w, about 30% w / w to about 95% w / w, about 30% w / w to about 80% w / w, or 55% w / w to about 65% w / w The composition according to any one of claims 1 to 10.   The amount of the polymer carrier is about 85% w / w to about 95% w / w, about 85% w / w to about 98% w / w, or about 90% w / w, relative to the total amount of the composition. 12. The composition of claim 11, wherein the composition is about 95% w / w.   The composition according to any one of claims 1 to 12, wherein the polymer carrier further comprises a further inert component selected from the group consisting of an anti-adhesive agent, a tackifier and a plasticizer.   14. The composition of claim 13, wherein the anti-adhesive is succinic acid.   The amount of the anti-adhesive agent is less than about 1% w / w, up to about 1% w / w, or up to about 5% w / w relative to the total amount of the composition. The composition as described.   14. The composition of claim 13, wherein the tackifier is composed of monomers that are insoluble in water and partially or wholly contain an acryl or methacrylic alkyl ether.   The tackifier is acrylic, N-butyl-methacrylic copolymer, acrylic methyl, acrylic 2-ethylhexyl copolymer, polyacrylic acid, methacrylic copolymer L, aminoalkyl methacrylate copolymer E, rosin ester, hydrogenated rosin, dipropylene glycol dibenzoate 14. The composition of claim 13, wherein the composition is selected from the group consisting of: a mixed hydrocarbon, and an acrylic copolymer.   The plasticizer is a phthalate, an ester of a polycarboxylic acid having a medium length linear or branched aliphatic alcohol, an acetylated monoglyceride, an alkyl citrate, a triethyl citrate (TEC), an acetyl triethyl citrate (ATEC). ), Tributyl citrate, (TBC), acetyl tributyl citrate (ATBC), trioctyl citrate (TOC), acetyl trioctyl citrate (ATOC), trihexyl citrate (THC), acetyl trihexyl citrate (ATHC) ), Butyryl trihexyl citrate (BTHC, trihexyl o-butyryl citrate), trimethyl citrate (TMC), methyl laurate, lauric acid, lauryl lactate, lauryl alcohol, alkylsulfonic acid phenyl ester, diethylene Glycol monoethyl ester, bis (2-ethylhexyl) phthalate (DEHP), diisooctyl phthalate (DIOP), bis (n-butyl) phthalate (DnBP, DBP), diisobutyl phthalate (DIBP), bis (2-ethylhexyl) adipate (DEHA), dimethyl adipate (DMAD), monomethyl adipate (MMAD), dioctyl adipate (DOA), ethyl oleate, sorbitan monooleate, glycerol monooleate, dibutyl sebacate (DBS), dibutyl maleate (DBM), Diisobutyl maleate (DIBM), benzoate, epoxidized vegetable oil, tris (tromethamine), N-ethyltoluenesulfonamide (o / pETSA), N- (2-hydroxypropyl) benzenesulfonamide (HP BSA), -(N-butyl) benzenesulfonamide (BBSA-NBBS), tricresyl phosphate (TCP), tributyl phosphate (TBP), triethylene glycol dihexanoate (3G6, 3GH), tetraethylene glycol diheptanoate ( 14. The composition of claim 13, selected from the group consisting of 4G7), 1,3-butylene glycol, dipropylene glycol, PEG400, Span80, and polyvinylpyrrolidone.   The inert carrier component is about 0.001% w / w to about 50% w / w, up to about 40% w / w, up to about 30% w / w, based on the total amount of the composition; The composition according to claim 13.   20. A composition according to any one of the preceding claims, wherein the composition contains a total of about 35% w / w anti-tackifier and tackifier relative to its total amount.   21. The composition of claim 20, wherein the anti-adhesive is succinic acid and the adhesive is dibutyl sebacate.   The amount of polymeric carrier and optional inert carrier component in the composition is about 50% w / w to about 99% w / w, about 80% w / w to about 98, relative to the total amount of the composition. 24. The composition of any one of claims 1-21, wherein the composition is% w / w, about 90% w / w to about 98% w / w, or about 95% w / w.   23. A composition according to any one of claims 1 to 22, further comprising one or more excipients.   24. Use of a composition as defined in any one of claims 1 to 23 in the production of a transdermal delivery patch for administration of a bioactive compound.   24. A transdermal delivery patch for the administration of a bioactive compound, comprising the composition as defined in any one of claims 1 to 23.   26. A transdermal delivery patch according to claim 25, wherein the composition is an individual or a semi-solid layer.   27. A transdermal delivery patch according to any one of claims 25 or 26, further comprising one or more occlusive or impermeable layers and / or one or more non-occlusive layers.   28. A transdermal delivery patch according to claim 27, wherein the impermeable or occlusive layer is a backing layer.   28. The transdermal delivery patch of claim 27, wherein the non-occlusive layer is a backing layer.   30. The transdermal delivery patch of claim 28 or 29, wherein the backing layer has a thickness of 0.0005 inches to about 0.01 inches.   28. The transdermal delivery patch of claim 27, wherein the impermeable layer is a removable release liner.   The impermeable layer is made of metal foil, Mylar (registered trademark), polyethylene terephthalate, siliconized polyester, fumed silica in silicone rubber, polytretrafluoroethylene, cellophane, siliconized paper, aluminized paper, polyvinyl chloride film , Ester foil, polyester terephthalate, composite foil or film containing polyester or aluminized polyester, polytetrafluoroethylene, polyether block amide copolymer, polyethylene methyl methacrylate block copolymer, polyurethane, polyvinylidene chloride, nylon, silicone elastomer, rubber base poly Isobutylene, styrene, styrene butadiene, and styrene isoprene copolymers, polyethylene, polypropylene, or Is formed from the combination, transdermal delivery patch according to claim 27.   33. The transdermal delivery patch of claim 31 or 32, wherein the release liner has a thickness of about 0.01 mm to about 2 mm.   34. The transdermal delivery patch of any one of claims 25-33, further comprising an adhesive layer.   The adhesive layer is a polymer adhesive selected from the group consisting of a polyacrylate polymer, a rubber base adhesive, and a polysiloxane adhesive; a commercially available adhesive selected from the group consisting of a polyacrylate adhesive. 34. Transdermal delivery patch according to 34.   36. The transdermal delivery patch according to any one of claims 25 to 35, wherein the bioactive compound is selected from the group consisting of drugs, cosmetics, nutritional supplements and nutrients.   Cardiovascular agent, antihypertensive agent, calcium channel blocker or calcium antagonist, and antiarrhythmic agent; congestive heart disease drug; cardiotonic agent; vasodilator; ACE inhibitor; diuretic; carbonic anhydrase Inhibitors; cardiac glycosides; phosphodiesterase inhibitors; alpha blockers; beta blockers; sodium channel blockers; potassium channel blockers; beta adrenergic agonists; platelet inhibitors; angiotensin II antagonists; anticoagulants; Anti-coagulant drug; thrombolytic agent; treatment of bleeding; treatment of anemia; thrombin inhibitor; anti-parasitic agent; antibacterial agent; insulin; human growth hormone and peptide; vaccine; Inflammatory drugs, especially non-steroidal anti-inflammatory drugs (NSAIDs) COX-2 inhibitors; steroidal anti-inflammatory drugs; prophylactic anti-inflammatory drugs; anti-glaucoma drugs; mast cell stabilizers; mydriatic drugs; drugs that affect the respiratory system; allergic rhinitis drugs; α-adrenergic agonists Drugs; corticosteroids; pharmaceuticals for chronic obstructive pulmonary disease; xanthine-oxidase inhibitors; anti-arthritic drugs; gout treatment; ortachoids and ortachoid antagonists; antimycobacterial agents; antifungal agents; Antiviral drugs specifically for respiratory, herpes, cytomegalovirus, human immunodeficiency virus and hepatitis infection; treatment of leukemia and Kaposi's sarcoma; especially anesthetics and analgesics, opioid receptor agonists, opioid receptor partial agonists, opioids An opioid containing an antagonist or agonist-antagonist mixed opioid receptor Pain control agents; tranquilizers; sympathomimetic drugs; adrenergic agonists; drugs that affect neurotransmitter uptake or release; anticholinergic drugs; antihemorrhoid treatment; radiation prevention or treatment Or drugs for chemotherapy; lipogenesis drugs; fat reduction therapy; anti-obesity peptides; anti-obesity drugs such as lipase inhibitors; sympathomimetics; treatments for gastric ulcers and inflammation such as proton pump inhibitors; Gins; VEGF inhibitors; Antihyperlipidemic agents, especially statins; antipsychotics, antiepileptics and anticonvulsants (anticonvulsants), psychotropics, stimulants, anxiolytics and hypnotics, antidepressants Drugs that affect the central nervous system (CNS) such as drugs; antiparkinsonian drugs Hormones such as sex hormones and fragments thereof; growth hormone antagonists; gonadotropin releasing hormones and analogs thereof; steroid hormones and antagonists thereof; selective estrogen modulators; growth factors; insulin, insulin fragments, insulin analogs, glucagons; Anti-diabetic drugs such as peptides and hypoglycemic agents; H1, H2, H3 and H4 antihistamines; natural proteins, peptides, oligonucleotides and nucleic acids and analogs, fragments and variants of such compounds; for treating migraine Drugs for asthma; drugs for asthma; cholinergic antagonists; glucocorticoids; androgens; antiandrogens; adrenocorticoid biosynthesis inhibitors; Anti-thyroid drugs such as phosphonates; antithyroid drugs; sunscreens, sun protectants and filters; cytokine agonists; cytokine antagonists; anticancer drugs; anti-Alzheimer drugs; HMGCoA reductase inhibitors; Cholesterol absorption inhibitors; HDL cholesterol raising agents; triglyceride reducing agents; anti-aging or anti-wrinkle agents; precursor molecules for hormone production; proteins such as collagen and elastin; antibacterial agents; anti-acne agents; Hair treatments and whitening agents; sunscreens, sun protectants and filters; human apolipoprotein variants; precursor molecules for hormone production; tampers Nutrients including amino acids; plant extracts such as grape seed extract; DHEA; isoflavones; vitamins, phytosterols and iridoid glycosides, sesquiterpene lactones, terpenes, phenolic glycosides, triterpenes, hydroquinone derivatives, phenylalkanones Antioxidants such as retinol and other retinoids including retinoyl acid and coenzyme Q10; omega-3 fatty acids; glucosamine; nucleic acids, oligonucleotides, antisense drugs; enzymes; cytokines; cytokine analogs; cytokine agonists; Antibody; antibody drug; gene therapy; lipoprotein; erythropoietin; vaccine; allergy / asthma, arthritis, cancer, diabetes, growth From disorders, cardiovascular diseases, inflammation, immune diseases, alopecia, pain, ophthalmic diseases, epilepsy, gynecological diseases, central nervous system diseases, viral infections, bacterial infections, parasitic infections, GI diseases, obesity, and blood diseases 40. The transdermal delivery patch of claim 36, selected from the group consisting of:   The bioactive compound is from alprazolam, donepazil, rispiredone, lorazepam, nicotine, lidocaine, diclofenac, felodipine, insulin, ketralac, prilocaine, halobetasol, hydrocortisol, opioids including oxycodone, and dihydrohydroxycodeinone (oxycodone base) 38. The transdermal delivery patch of claim 37, selected from the group consisting of:   The amount of the bioactive compound is about 0.1% w / w to about 30% w / w, up to about 20% w / w, up to about 10% w / w, relative to the total amount of the composition. 39. A transdermal delivery patch according to any one of claims 25-38.   40. The transdermal delivery patch of claim 39, wherein the amount of the bioactive compound is from about 3.0% w / w to about 15.0% w / w relative to the total amount of the composition.   41. Transdermal delivery according to any one of claims 25 to 40, wherein the ratio of bioactive compound: TP (% w / w) is from about 5: 5 to about 5: 0.5, or about 5: 1. patch.   41. The ratio of the polymeric carrier: (bioactive compound and TP) is from about 1: 1 to about 3: 1, or from about 7: 6 to about 7: 3. Transdermal delivery patch. A method of preparing a transdermal delivery patch for administration of a bioactive agent comprising:
(i) combining the polymer carrier and any inert single component with a suitable solvent;
(ii) combining a dispersion containing a physiologically active compound and a phosphate compound of tocopherol with the product of (i);
(iii) stirring the product of (ii) until completely uniform;
(iv) placing the composition of (iii) on the surface of a suitable mold or casting;
(v) drying the composition under heating conditions;
Said method.   44. The method of claim 43, wherein the drying is performed at 90 ° C or less, from about 30 ° C to about 90 ° C, or about 75 ° C.   45. The method of claim 44, wherein the drying is performed for about 0.5 to about 24 hours.

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